Photoacid compounds, and related compositions, methods and systems

ABSTRACT

A photoacid compound having a light absorbing moiety attaching a payload moiety through a linker, in which the linker comprises a geminal dialkyl linked to a carbonyl group attaching the payload moiety, and the linker is configured to present the carbonyl oxygen for reaction with a hydroxyl group presented on the light absorbing moiety in ortho position to the linker.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 61/568,046, entitled “Long Wavelength activation of bioactivecompounds” filed on Dec. 7, 2011 with docket number CIT-6041-P, and isrelated to PCT application Ser. No. ______ entitled “Caged compounddelivery and related compositions, methods and systems” filed on Dec. 7,2012, with docket number P1130-PCT2, each of which is incorporatedherein by reference in its entirety.

FIELD

The present disclosure relates to compounds capable to deliver a payloadin a controlled fashion. In particular, the present disclosure relatesto photoacid compounds and related compositions methods and systems.

BACKGROUND

Molecular delivery has been a challenge in the field of moleculeanalysis, in particular when aimed at obtaining controlled delivery ofanalytes of interest to specific environments. Whether for chemical,biological or medical applications or for fundamental studies, severalmethods are commonly used for the delivery of various classes ofcompounds including biomaterials and biomolecules.

Controlled delivery of targets to specific environments, e.g. deliveryof pesticides, delivery of chemicals such as a fluorescent dye on abiological or non-biological system, such as specific cell types and/ortissues of individuals in vitro and/or in vivo is currently stillchallenging, especially when directed at providing controlled release ofthe target in a controllable conformation, typically associated to abiological or chemical activity.

SUMMARY

Described herein are photoacid compounds and related compositions,methods, and systems that in some embodiments permit the uncaging andrelease of a payload molecule upon irradiation with a suitablewavelength light.

According to a first aspect, a photoacid compound is described. Thephotoacid compound comprises a light absorbing moiety attaching apayload moiety through a linker moiety. In the photoacid compound, thelinker moiety comprises a geminal dialkyl moiety linked to an estergroup having a carbonyl oxygen, the carbonyl group of the esterattaching the payload moiety. In the photoacid compound, the lightabsorbing moiety attaches the linker moiety in ortho position to ahydroxyl group and the linker is configured to present the carbonyloxygen for reaction with the hydroxyl group.

According to a second aspect, a photoacid compound is described, thephotoacid having the general structure according to formula (I):

wherein:

-   -   R⁴ is a light-absorbing moiety presenting a hydroxyl group for        interaction with the carbonyl oxygen of the R³(CO)O group,        wherein the light-absorbing moiety is a substituted or        unsubstituted polycyclic aromatic hydrocarbon, a substituted or        unsubstituted closed chain cyanine, or a substituted or        unsubstituted hemicyanine, and wherein the hydroxyl group is        covalently bonded to the polycyclic aromatic hydrocarbon, the        closed chain cyanine, or the hemicyanine, and the hydroxyl group        is in a position ortho to X¹;    -   R³ is a payload moiety, wherein the payload moiety is a        substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy,        alkylamino, or dialkylamino moiety;    -   X¹ is independently selected from the group consisting of C and        O;    -   m is between 0 and 3; and    -   R¹ and R² are independently C₁-C₆ alkyl groups, cycloalkyl, or        substituted or unsubstituted hydrocarbylene groups wherein when        R¹ and R² are substituted or unsubstituted hydrocarbylene R¹ and        R² they are linked together to form a cyclic moiety.

According to a third aspect, a method to deliver a compound isdescribed, the method comprises providing a caged compound, the cagedcompound being caged as a payload moiety within the photoacid compoundherein described and in particular with a photoacid compound of Formula(I), the photoacid compound being in a ground state in which thehydrogen substituted heteroatom presented on the light absorbing moietyof the photoacid compound has a ground state pK_(a). The method foruncaging the caged compound by irradiating the photoacid compound withlight at a wavelength suitable to promote the photoacid compound to anexcited state wherein the hydrogen substituted heteroatom presented onthe light absorbing moiety of the photoacid compound has an excitedstate pK_(a) lower than the ground state pK_(a).

According to a fourth aspect, a system to deliver a compound isdescribed, the system comprising at least two of: one or more photoacidscompounds, and in particular one or more photoacid compounds of Formula(I) and a light source suitable to irradiate light at a suitablewavelength, for simultaneous, combined or sequential use in methodsherein described.

Photoacid compounds herein described and related compositions, methodsand systems allow in several embodiments controlled release of a payloadmoiety in various chemical and biological environments. In particular,in several embodiments, photoacid compounds herein described and relatedcompositions methods and systems allow controlled release of a payloadmoiety upon irradiation at a wavelength of at least about 750 nm orhigher.

Photoacid compounds herein described and related compositions, methodsand systems can be used in connection with applications whereincontrolled delivery of a compound is desired. Exemplary applicationscomprise applications in medical field, biological and chemicalresearch, such as drug development, molecule studies, light-activatedtherapies and strategies for imaging biological systems.

The details of one or more embodiments of the disclosure are set forthin the accompanying drawings and the description below. Other featuresand objects will be apparent from the description and drawings, and fromthe claims.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated into and constitute apart of this specification, illustrate one or more embodiments of thepresent disclosure and, together with the description of exampleembodiments, serve to explain the principles and implementations of thedisclosure.

FIG. 1 shows a schematic illustration of photoacid compounds hereindescribed and of related methods and systems. In particular FIG. 1Ashows a schematic representation of a method to uncage a drug comprisedas a payload in photoacid compound wherein the light absorbing moiety isformed by a NIR absorber. FIG. 1B shows a known reaction scheme ofuncaging of a water molecule in a photoacid after protonation of ahydroxyl group wherein the protonation is induced by the increase inacidity of the photoacidic hydrogen. FIG. 1C shows a schematic of thenovel protonation of a carbonyl group in a linking moiety and subsequentuncaging of a payload moiety of a generic photoacid compound afterirradiation of the light absorbing moiety with light resulting in anincrease in the acidity of the photoacidic proton. FIG. 1D shows theuncaging of a particular photoacid compound by irradiation of thephotoacid compound with light resulting in the release of hydrocinnamicacid. FIG. 1E shows a schematic structure of an exemplary genericphotoacid compound with an acene light absorbing moiety in whichexpansion of the acene chromophores allows absorption of a longerwavelength light. FIG. 1F shows an exemplary photoacid compound asherein described with a retinal/carotene-type light absorbing moiety.FIG. 1G shows an exemplary photoacid compound as herein described with acyanine-type light absorbing moiety. FIG. 1 H shows the uncaging of aparticular photoacid compound by irradiation of the photoacid compoundwith light resulting in the release of γ-aminobutyric acid withconcomitant decarboxylation to release CO₂.

FIG. 2 shows a schematic of a ring opening reaction of a fluoresceinmolecule that results in fluorescence.

FIG. 3 shows a schematic of a synthetic scheme for the synthesis ofphotoacid compounds with a naphthol-based light absorbing moiety.

FIG. 4 shows a schematic of a synthetic scheme for the synthesis ofphotoacid compounds with a cyanine-based light absorbing moiety.

FIG. 5 shows a schematic of a synthetic scheme for the synthesis ofphotoacids with a cyanine-based light absorbing moiety.

FIG. 6 shows LC-MS traces for an exemplary photoacid compound as hereindescribed before and after irradiation with light to uncage the payloadmoiety.

FIG. 7 shows a schematic of a synthetic scheme for the synthesis of aphotoacid compound with X¹ is C.

FIG. 8 shows a schematic of general synthetic schemes for the synthesisof cyanine-based photoacid compounds as herein described. FIG. 8A showsa general synthetic strategy to synthesize photoacid compounds ofFormula (I) using a common precursor (ortho dihydroxyarene; 32). FIG. 8Bshows a general synthetic scheme for the synthesis of closed chaincyanines with a variable-length polyene and variable heteroaryl groups.FIG. 8C shows an exemplary application of the synthesis shown in FIG. 8Bto the general synthesis of photoacid compounds with cyanine lightabsorbing moieties. FIG. 8D shows a photoactive molecule with aparticular desired absorbance wavelength (compound 40) and an analogousphotoactive compound as herein described (compound 41) incorporatingcompound 40 as the light absorbing moiety. FIG. 8E shows the synthesisof a quinolinium compound that can be used in the synthesis of cyanines.FIG. 8D shows a photoactive molecule with a particular desiredabsorbance wavelength (compound 40) and an analogous photoactivecompound as herein described (compound 41) incorporating compound 40 asthe light absorbing moiety.

DETAILED DESCRIPTION

Described herein are photoacid compounds and related compositions,methods, and systems that in some embodiments permit the uncaging andrelease of caged payload molecules upon irradiation with long wavelengthlight.

The term “photoacid” as used herein refers to a compound that can beswitched from a ground state to an excited state upon absorption oflight, and that has an excited state acidity associated to the excitedstates higher than a ground state acidity associated to the groundstate. The term “excited state” as used herein refers to an electronicstate of a moiety in which the molecule has absorbed light energy andbeen promoted to a higher energy state. This process is referred to as“excitation.” The term “ground state” refers to the electronic state ofa moiety in which the electrons are in their lowest energy molecularorbitals. In photoacid compounds, the excitation can be accomplished,for example, by irradiating a photoacid molecule with light of energyequal to the difference in energy between the ground state and theexcited state. The energy of the light is determined by the wavelengthof the light according the relationship E=hc/λ, where E is the energy ofthe photon, h is Plank's constant, and λ is the wavelength of the light.In particular, in some embodiments, the light used to effect theexcitation is infrared or near infrared light.

In particular, molecules that can undergo excitation to an excited stateare typically molecules comprising systems of conjugated π bonds such asthose present in polyaromatic (e.g. polycyclic aromatic hydrocarbons)and polyene (e.g. cyanine and carotene molecules) molecules. Inparticular, the energy required to excite a molecule such as a photoacidcan be decreased, which results in light of longer wavelengths beingable to excite the molecule, by increasing the size of the system ofconjugated π bonds (see, e.g., [Ref 1]).

Determination of the excited states for a certain compound and therelated level of energy can be performed by a skilled person usingmethods and techniques identifiable by a skilled person. By way ofexample, the excited states can be determined by measuring theabsorption spectrum of a compound and thus the wavelengths of lightabsorbed by the compound via spectrophotometry.

In particular, a “photoacid” in the sense of the present disclosuretypically comprises a light absorbing moiety presenting an hydrogensubstituted heteroatom. A shift in acidity following light absorbance bythe light absorbing moiety can be detected by detecting the pK_(a) of ahydrogen substituted heteroatom which is presented on the lightabsorbing moiety of the photoacid. Detection of the pK_(a) of thehydrogen substituted heteroatom can be performed according to techniquesand methods identifiable by a skilled person (see e.g. [Ref 2] and [Ref3]). Exemplary photoacids include hydroxyaryls such as 2-naphthol whichdisplays a ground state pK_(a) of 9.5 and an excited state pK_(a)(pK_(a)*) of 2.8 (see, e.g., [Ref 4]). The pK_(a)* of a photoacid can bedetermined, for example, by combining the Förster cycle with the pK_(a)of the photo acid in its ground state to perform calculations known tothose in the art, as well as by fluorescence titrations (see, e.g., [Ref2] and [Ref 3]).

In embodiments herein described, the photoacid compound of thedisclosure comprise a light absorbing moiety which is attached to apayload moiety through a linker comprising a geminal dialkyl moietywhich presents a carbonyl group attaching the payload moiety. Inparticular, in photoacid compounds of the disclosure the linker isconfigured to present the carbonyl oxygen in proximity to the hydroxylof the light absorbing moiety and is further configured such that thehydroxy is ortho to the linker.

The term “attach” or “attached” as used herein, refers to connecting oruniting by a covalent bond in order to keep two or more componentstogether, which encompasses either direct or indirect attachment where,for example, a first moiety is directly bound to a second moiety, or oneor more intermediate moieties are disposed between the first moiety andthe second moiety.

The term “present” as used herein with reference to a compound orfunctional group indicates attachment performed to maintain the chemicalreactivity of the compound or functional group as attached. Accordingly,for example a carbonyl group presented on a linker, is able to performunder the appropriate conditions the one or more chemical reactions thatchemically characterize the carbonyl group. The wording “present forreaction”, with reference to a compound or a functional group indicatesattachment performed to maintain the chemical reactivity of the compoundor functional group as attached, such that the attachment is performedin a configuration that allow the specific reaction mentioned.Accordingly, a carbonyl group presented for reaction with an hydroxylgroup indicates a configuration in which the carbonyl group is in aposition allowing a chemical reaction with the hydroxyl group.

The term “light absorbing moiety” as used herein indicates moiety thatis converted to an excited states upon absorption of light at apredetermined wavelength. Exemplary light absorbing moieties compriselong wavelength absorbing moieties (LWAP) able to absorb light at awavelength greater than or equal to 750 nm, and more particularly awavelength in a range from about 900 to about 1100 nm. Additionalexemplary light absorbing moieties comprise short wavelength lightabsorbing moieties (SWAP) able to absorb light at a wavelength less than750 nm and in particular at a wavelength from about 500 nm to about 750nm and a wavelength from about 600 nm to about 750 nm.

In some embodiments, the light absorbing moiety comprises a substitutedor unsubstituted polycyclic aromatic hydrocarbon or substituted orunsubstituted closed chain cyanine or hemicyanine dye presenting ahydroxyl group in which the hydroxyl group is covalently bound to thesubstituted or unsubstituted polycyclic aromatic hydrocarbon orsubstituted or unsubstituted closed chain cyanine or hemicyanine dye. Inparticular, in some embodiments, the hydroxyl group can be covalentlybound to a carbon of the substituted or unsubstituted polycyclicaromatic hydrocarbon or substituted or unsubstituted closed chaincyanine or hemicyanine dye such that the hydroxyl is ortho to the linkerherein described.

The term “linker” as used herein indicates to an organic structureconfigured to connect two moieties to form a stable chemical structure.In particular, linker in the sense of the present disclosure can beformed by a mono or dialkoxy moiety comprising the dialkyl germinalgroup and presenting the carbonyl group for reaction.

The term “payload” as used herein refers to a moiety carried by acompound in a configuration that allows the relevant delivery undercontrollable parameters. In particular, in embodiments herein describeda payload is a moiety is connected to the linker and forms part of thephotoacidic compounds herein described. In particular in embodimentsherein a payload indicates an organic moiety configured to attach thecarbonyl group of the linker of a photoacid compound herein described.

In particular, in some embodiments, a photoacid compound hereindescribed has of the general structure according to Formula (I):

wherein:

-   -   R⁴ is a light-absorbing moiety presenting a hydroxyl group for        interaction with the carbonyl oxygen of the R³(CO)O group,        wherein the light-absorbing moiety is a substituted or        unsubstituted polycyclic aromatic hydrocarbon, a substituted or        unsubstituted closed chain cyanine, or a substituted or        unsubstituted hemicyanine, and wherein the hydroxyl group is        covalently bonded to the polycyclic aromatic hydrocarbon, the        closed chain cyanine, or the hemicyanine, and the hydroxyl group        being in a position ortho to X¹;    -   R³ is a payload moiety, wherein the payload moiety is a        substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy,        alkylamino, or dialkylamino moiety; and    -   X¹ is independently selected from the group consisting of C and        O;    -   m is between 0 and 3; and    -   R¹ and R² are independently C₁-C₆ alkyl groups, cycloalkyl, or        substituted or unsubstituted hydrocarbylene groups wherein when        R¹ and R² are substituted or unsubstituted hydrocarbylene groups        they are linked together to form a cyclic moiety.

In particular, in the photoacid compound of formula (I) and otherembodiments herein described, the moiety of Formula (II)

is the linker.

In particular, in some embodiments, R⁴ can be a moiety of Formula (III):

wherein n is between 0 and 5.

In particular, in some, R⁴ can be a moiety of Formula (IV):

where n is between 0 and 5, and m is between 1 and 3.

In particular, in some embodiments, R⁴ can be a moiety of Formula (V):

wherein R^(a) and R^(b) are independently H, alkyl, or O-alkyl; Y is N,O, or S; and p is between 1 and 4.

In particular, in some embodiments, R⁴ can be a moiety of Formula (VI):

wherein R^(c) and R^(d) are independently alkyl and q is between 1 and4.

In particular, in some embodiments, R⁴ can be a moiety of Formula (VII):

wherein r is between 1 and 4.

In particular, in some embodiments, R⁴ can be a moiety of Formula(VIII):

A skilled person will understand, upon a reading of the presentdisclosure, that the light absorbing moiety and herein described can besubstituted or unsubstituted and in particular have additionalsubstituents which can be added to impart additional functionalitiessuch as, for example, hydrophilic substituents (e.g. sulfonate, and inparticular polysulfonates such as polysulfonate peptides oroligopeptides, as well as polyethylene glycol groups), and functionalgroups and/or moieties to connect the photoacid compounds hereindescribed to other molecules and/or substances (e.g. for connection tocarbon nanotubes, fullerenes, antibodies, polymers, proteins, lipids,carbohydrates, and others identifiable to a skilled person).

In embodiments herein described the photoacid attaches a payload and inparticular a payload R³ in a photoacid of Formula (I).

In particular, R³ can be an organic moiety such as, for example asubstituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy,alkylamino, or dialkylamino moiety. In some embodiments, and inparticular in embodiments where R³ is a substituted or unsubstitutedalkyl, aryl, heteroaryl molecule, R³ is adapted to exist in a carboxylicacid form wherein the carboxylic acid form can be used to provide thecarbonyl group of the linker of Formula (II) (see Example 1 and Example3).

In particular, in some embodiments, R³ can be a moiety of Formula (IX):

wherein q is between 0 and 5, R^(α) is H, or substituted orunsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy,heteroaryl, hetroarylamino, and heteroaryloxy; X is C or N; and whereinwhen q is greater than 1, each R′ is independent of the other R^(α)substituents.

In particular, in some embodiments wherein R³ is according to Formula(IX), R³ can be selected from the group consisting of Formulas(X)-(XII):

In particular, in some embodiments, R³ can be a moiety of Formula(XIII):

wherein n is between 1 and 5, R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; andwherein when n is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.

In particular, in some embodiments wherein R³ is according to Formula(XIII), R³ can be selected from the group consisting of Formulas (XIV)and (XV):

In particular, in some embodiments, R³ can be a moiety of Formula (XVI):

wherein p is between 1 and 5, R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy;wherein R^(δ) is H, substituted or unsubstituted alkyl, acyl, aryl; andwherein when p is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.

In particular, in some embodiments wherein R³ is according to Formula(XVI), R³ can be of Formula (XVII):

In particular, in some embodiments wherein R³ is according to Formula(XVI) and R^(δ) is acyl, R³ can be a peptide or oligopeptide such thatthe peptide or oligopeptide is attached to the linker via the N-terminusof the peptide or oligopeptide.

In particular, in some embodiments, R³ can be a moiety of Formula(XVIII):

wherein m is between 1 and 5, R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; andwherein when m is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.

In particular, in some embodiments, R³ can be a moiety of Formula (XIX):

wherein q is between 0 and 4, R^(α) is H, or substituted orunsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy,heteroaryl, hetroarylamino, and heteroaryloxy; c is a substituted orunsubstituted hydrocarbylene, X is C or N; and wherein when q is greaterthan 1, each R^(α) is independent of the other R^(α) substituents.

In some embodiments, the payload moiety and in particular the payloadmolecule R³ is a molecule for which controlled disconnection and releasefrom the photoacid compound is desired. Exemplary payload moleculesinclude imaging agents, drug molecules, fluorescent dyes, pesticides,pigments, neurotransmitter; anti-cancer agents; sedatives; antibodies;protein therapeutics and others identifiable to a skilled person upon areading of the present disclosure.

In some embodiments herein described the payload R³ can be attached toR⁴ through the linker of formula (II). In particular in the linker offormula (II), X¹ can be independently O or C.

In some embodiments, R¹ and R² are methyl groups or other C₁-C₆ alkylgroups or cycloalkyl. In other embodiments, R¹ and R² are linked to forma cyclic moiety such as a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (III); and the linker is a linker of Formula(II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked togetherto form a cyclopentyl or cyclohexyl moiety. In particular, in otherembodiments the light absorbing moiety R⁴ is a moiety according toFormula (III), the linker is a linker of Formula (II) wherein X¹ is Cand R¹ and R² are methyl, ethyl, or linked together to form acyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (III) wherein n is 0; and the linker is alinker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl,or linked together to form a cyclopentyl or cyclohexyl moiety. Inparticular, in other embodiments the light absorbing moiety R⁴ is amoiety according to Formula (III) wherein n is 0, the linker is a linkerof Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, orlinked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (IV); and the linker is a linker of Formula(II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked togetherto form a cyclopentyl or cyclohexyl moiety. In particular, in otherembodiments, the light absorbing moiety R⁴ is a moiety according toFormula (IV); and the linker is a linker of Formula (II) wherein X¹ is Cand R¹ and R² are methyl, ethyl, or linked together to form acyclopentyl or cyclohexyl moiety

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (IV) wherein m is 2 and n is 0; and thelinker is a linker of Formula (II) wherein X¹ is O and R¹ and R² aremethyl, ethyl, or linked together to form a cyclopentyl or cyclohexylmoiety. In particular, in other embodiments, the light absorbing moietyR⁴ is a moiety according to Formula (IV) wherein m is 2 and n is 0; andthe linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² aremethyl, ethyl, or linked together to form a cyclopentyl or cyclohexylmoiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (V); and the linker is a linker of Formula(II) wherein X¹ is 0 and R¹ and R² are methyl, ethyl, or linked togetherto form a cyclopentyl or cyclohexyl moiety. In particular, in otherembodiments, the light absorbing moiety R⁴ is a moiety according toFormula (V); and the linker is a linker of Formula (II) wherein X¹ is Cand R¹ and R² are methyl, ethyl, or linked together to form acyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VI), and the linker is a linker of Formula(II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked togetherto form a cyclopentyl or cyclohexyl moiety. In particular, in otherembodiments, the light absorbing moiety R⁴ is a moiety according toFormula (VI); and the linker is a linker of Formula (II) wherein X¹ is Cand R¹ and R² are methyl, ethyl, or linked together to form acyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VI) wherein q is 2, and the linker is alinker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl,or linked together to form a cyclopentyl or cyclohexyl moiety. Inparticular, in other embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VI) wherein q is 2; and the linker is alinker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl,or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VII), and the linker is a linker of Formula(II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked togetherto form a cyclopentyl or cyclohexyl moiety. In particular, in otherembodiments, the light absorbing moiety R⁴ is a moiety according toFormula (VII); and the linker is a linker of Formula (II) wherein X¹ isC and R¹ and R² are methyl, ethyl, or linked together to form acyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VII) wherein r is 2, and the linker is alinker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl,or linked together to form a cyclopentyl or cyclohexyl moiety. Inparticular, in other embodiments, the light absorbing moiety R⁴ is amoiety according to Formula (VII) wherein r is 2; and the linker is alinker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl,or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, one or more hydrophilic substituentthat can be added to the light absorbing moiety and/or can be comprisedin the payload moiety to provide or increase a desired water solubility.

In embodiments herein described, the photoacid compounds of thedisclosure can be used in methods and systems to deliver the payload R³in a controlled fashion.

In particular, a payload R³ can be released or decaged by providing thelight absorbing moiety of the photoacid with a wavelength suitable toswitch the state of the light absorbing moiety R⁴ from a ground state toan excited state.

The term “cage” as used herein relates to the interaction between afirst chemical moiety and a second chemical moiety that minimizes theparticipation in physical chemical or biological reactions of the secondchemical moiety. In particular, the payload is caged by the linkermoiety through covalent bond of the carbonyl group of the linker with asuitable functional group in the linker. The terms “decage” or “uncage”herein are defined as a modification of a caging interaction between afirst and second chemical moiety to the chemical moiety, formingliberating the second molecule to participate in chemical or biologicalreactions. In embodiments herein described, decaging is performedthrough cleavage of the covalent bond between carbonyl group and thepayload. Decaging of a compound can be detected by identifying thedecaged activity of the uncaged compound or by LC-MS spectroscopy toidentify either the caged compound, the first moiety, or the secondmoiety.

Determination of a suitable wavelength to perform the switching from aground state to an excited state can be performed by a skilled personbased on the structural and chemical properties of the light absorbingmoiety. For example, in some embodiments, a suitable wavelength can beselected based on known photoactive molecules (e.g. polycyclic aromatichydrocarbons and/or cyanine; see, e.g., [Ref 1]) which can then besubjected to the appropriate preparation methods exemplified in Examples1-4 and Examples 7-8.

In embodiments of photoacids of the present disclosure, the wavelengthis selected so that the promotion of the light absorbing moiety R⁴ froma ground state to an excited state results in a decrease of the pK_(a)of the photoacidic R⁴OH group relative to the pK_(a) of the same OHgroup in the ground state. The consequent shifting of the acid baseequilibrium of the photoacid results in the release of payload R³.Accordingly, detection of the successful switching to an excited stateby the light absorbing moiety R⁴ following irradiation of the photoacidswith a suitable wavelength can be performed by detecting a switching inacidity in the reaction solution performed by measuring pK_(a) of thephotoacidic R⁴ hydroxyl group.

Accordingly, according to methods and systems herein described,providing a caged compound can be performed by synthesizing a photoacidof Formula (I) including the compound caged as a payload moiety. Thephotoacid compound is selected to have a light absorbing moiety with aOH group such that upon irradiation with light at a wavelength excitingthe light absorbing moiety the pK_(a) of the OH group is lowered.

In some embodiments, the light absorbing moiety can be formed by a LWAPwhich is promoted to an excited state upon irradiation with an infraredlight or a near infrared light (or NIR). The term “infrared light” asused herein refers to light in the infrared region of theelectromagnetic spectrum from approximately 0.75 μm to 1000 μm. The term“near infrared” refers to a region of the infrared spectrum fromapproximately 0.75 μm (750 nm) to 1.4 μm (1400 nm).

In this connection, reference is made to the schematic illustration ofFIG. 1 in which the FIG. 1A presents a schematic illustration of a lightactivated photoacid releasing according to the present disclosure, wherea long-wavelength absorber is linked to the exemplary payload moietyformed by a drug, the drug being replaceable by an imaging agent orother payload molecule as will be understood by a skilled person. FIG.1B shows a UV-activated photoacid releasing water, through photoactiveprotonation of an hydroxyl alcohol presented by a naphthyl moietyresulting in the release of water to be considered in comparison withFIG. 1C showing an exemplary light activated photoacid releasingaccording to the present disclosure in which the light absorbing moietyis a napthol. In FIG. 1C, the system is designed to have a photoacidicgroup (the OH), and an ester that can intramolecularly hydrogen bond tothe OH. In FIG. 1C, excitation with light can increase the acidity ofthe OH, and a proton transfer occurs. In the illustration of FIG. 1C,the ester is a derivative of a t-butyl ester, a class that is especiallysensitive to acid-catalyzed ester cleavage. t-Butyl esters suitable forinclusion in a linker herein described comprise t-butyl esters commonlyused in commercial solid phase peptide synthesizers and t-butyl estersthat are part of the common Boc protecting group. In particular, inseveral suitable t-butyl esters, the standard t-butyl cleavage mechanismcan produce a generic carboxylate. In the illustration of FIG. 1C,cleavage in this system releases the generic entity RCO₂H, a carboxylicacid, which, under physiological conditions will be in its deprotonated,carboxylate form (structure in box). Computational studies show that theintramolecular hydrogen bond shown in FIG. 1C is viable.

In some compounds herein described, the photochemical excited state canincrease the acidity of appropriate groups by as many as 10 orders ofmagnitude ([Ref 5] and [Ref 6]). Such an increase in acidity isintramolecular and hence usually does not alter the pH of thesurrounding environment. In some embodiments, the shift in acidity(pK_(a)) of about 10 orders of magnitude is corresponds to only anenergy change of <14 kcal/mol, which supports the conclusion thatsuitable light absorbing moiety for the photoacid compounds hereindescribed can absorb a very long wavelength light (e.g. from about 900to about 1100 nm) and that various moiety that can be excited at longwavelength are expected to be able to initiate photoacid chemistry. Forexample, light at 1010 nm has an energy of 28 kcal/mol, twice what isneeded to produce the desired pK_(a) shift.

FIG. 1D shows a proof of concept establishing viability of the essentialphotochemical reaction proposed (see also Example 5 showing thatirradiation produces the carboxylic acid shown). FIG. 1E shows how thelight-absorbing feature of the molecule—the chromophore—can be variedwhile leaving the essential chemistry intact. As the chromophore getslarger, it can absorb longer wavelength light such as, for example, longwavelength visible light and/or NIR light. Even at wavelengths far outinto the NIR, enough energy can be present to enhance the pK_(a) of theOH. For example, light at 1010 nm (commonly used in optical coherencetomography) has an energy of 28 kcal/mol, twice what is needed or afactor of 10 orders of magnitude.

The light absorbing moieties described herein can be selected to absorblonger wavelengths of light. In some instances, known dyes and NIRabsorbers, can permit empirical determination which systems are mosteffective (see, for example, [Ref 1]). FIG. 1F shows aretinal/carotene-type compound that can be continuously tuned by justincreasing the number of double bonds. In this approach, the moleculeleft after uncaging resembles carotene or vitamin E, and can exertnon-toxic activity. FIG. 1G shows a merocyanine dye strategy. These arevery common, highly tunable structures that have seen extensivebiological use in the form of the common Cy and Alexa dyes ([Ref 7]) andpossess arene and heteroarene moieties suitable to the preparationreactions of Examples 1-4 and Examples 7-8.

The photochemistry illustrated by the exemplary illustration of FIG. 1can uncage compounds other than carboxylates. FIG. 1H shows uncaging ofan amine, in this particular case producing the inhibitoryneurotransmitter γ-aminobutyric acid (GABA). This strategy can be usedto uncage many compounds including, for example, neurotransmitters,anti-cancer agents, sedatives, antibodies, protein therapeutics, imagingmarkers, and others. By way of example, a compound such as etomidate canbe caged in several ways. The unfunctionalized N of the imidazole ringof etomidate can be acylated to produce a structure that can be acidcleaved. Alternative, carboxyl derivatives at C2 of etomidate (betweenthe two nitrogens) decarboxylate when hydrolyzed, feeding naturally intothe t-butyl ester strategy herein described. From the structure shownabove, the unfunctionalized N of the imidazole ring of etomidateprovides a handle for attaching a photocage.

The generality of the uncaging process herein described can permit thedevelop other probes and ways to monitor the efficiency of the system.For example, fluorescein is a common dye that is often used inbiological imaging. It exists in two forms that can interconvert (FIG.2). Either the carboxylic acid or the OH of the fluorescein could becaged within the photoacid compounds described herein. The cagedcompound would not be fluorescent. Photonic uncaging would liberatefluorescein, allowing an array of imaging strategies to evaluate theefficiency and localization of the photonic uncaging. Of course, manyother dyes and imaging agents could be manipulated in the same way.

In embodiments of the photoacid compounds herein described, thephotochemical excited state can increase the acidity of appropriategroups by as many as 10 orders of magnitude ([Ref 5] and [Ref 6]). Inthose embodiments, such an increase in acidity is intramolecular andhence does not alter the pH of the surrounding environment.

In some embodiments, a suitable wavelength provides an energy change of<14 kcal/mol and results in shifting an acid-base equilibrium (pK_(a))by 10 orders of magnitude. In particular in some embodiments, such ashift is associated to a wavelength of from about 900 to about 1100 nm).For example, light at 1010 nm has an energy of 28 kcal/mol, twice whatis needed to produce the desired pK_(a) shift. Additional embodimentswill be identifiable to a skilled person upon reading of the presentdisclosure.

In some embodiments, the photoacids are expected to be tunable withregard to lifetime and absorption spectrum. Often, the excited-statelifetimes of these molecules are short, which could limit the efficiencyof the proton-transfer reaction. However, several strategies forenhancing excited state lifetimes are known, including adding heavyatoms to facilitate conversion to the longer-lived triplet excitedstate. Additionally, the addition of electron-withdrawing substituentsat key points in the extended π system can create “super photoacids”which deprotonate very efficiently in aqueous solutions upon excitation.In some embodiments, photoacidic molecules can be based on 2-naphthols,which display the desired photoacid effect, have a good safety profile,and can be easily modified to control water-solubility and to the tunethe optical properties (see e.g. schematized in FIG. 1C and FIG. 1D).

In some embodiments, the long wavelength light used to uncage thepayload is infrared light. In particular, in some embodiments, theinfrared light is of a wavelength between 750 nm and 1400 nmcorresponding to near infrared light. In other embodiments the nearinfrared light used to uncage the payload compounds can be between 900and 1100 nm.

The method for and uncaging the caged compound by irradiating thephotoacid compound of Formula (I) with light at a wavelength suitable topromote the photoacid compound of Formula (I) to an excited statewherein the hydrogen substituted heteroatom presented on the lightabsorbing moiety of the photoacid compound has an excited state pK_(a)lower than the ground state pK_(a).

Irradiating can be performed through various procedures and techniquesidentifiable by a skilled person. In particular, a long wavelength lightcan be delivered by any of a number of means such as via microscope,endoscope, LCD panel or LED display as handheld or non-portable devicesor worn as glasses or other such attachment to the body. Imageintensifiers can be used to further increase the emitted power from suchdevices in order to activate the preparation of molecules.

Other approaches can use high intensity short wavelength light and aresuitable for applications in which use of the short length is desired.For example in a biological environment, use of a high intensity shortwavelength can be used in application wherein production of reactiveoxygen species or genetic manipulation of host cells is desired.

Photoacid compounds described herein can be provided as a part ofsystems to deliver compounds, identifiable by a skilled person uponreading of the present disclosure. In some embodiments, the systems fordelivery of the caged compounds herein described can be provided in theform of combinations of photoacid compounds and/or related compositions,in which the system can comprise one or more photoacid compounds, and asuitable vehicle identifiable by a skilled person.

In some embodiments, the systems herein described can be provided in theform of kits of parts. In a kit of parts, one or more photoacidcompounds herein described, and suitable light source and other reagentsto perform the reactions can be comprised in the kit independently. Thephotoacid compounds can be included in one or more compositions, andeach photoacid compounds can be in a composition together with asuitable vehicle.

The term “vehicle” as used herein indicates any of various media actingusually as solvents, carriers, binders or diluents for the cagedcompounds that are comprised in the composition as an active ingredient.

Further characteristics of the present disclosure will become moreapparent hereinafter from the following detailed disclosure by way orillustration only with reference to an experimental section.

EXAMPLES

The photoacid compounds, compositions methods and systems hereindescribed are further illustrated in the following examples, which areprovided by way of illustration and are not intended to be limiting.

In particular, the following examples illustrate exemplary photoacid inwhich the light absorbing moiety is formed by naphthol, and cyanine, X¹is an 0 or a C, R¹ and R² are either methyl or are linked to form acycloalkyl moiety and the payload hydrocinnamic acid and related methodsand systems. A person skilled in the art will appreciate theapplicability and the necessary modifications to adapt the featuresdescribed in detail in the present section, to additional photoacidcompounds, methods and systems according to embodiments of the presentdisclosure.

A skilled person will realize, upon a reading of the present disclosure,that compounds similar to those exemplified below can be made using thesynthetic methods herein described. A skilled person can select suitablestarting material based on the starting materials exemplified below byutilizing databases such as SCIFINDER® and REAXYS®. A skilled personwould also be able to use purification methods in addition to thoseexemplified below such as, for example, recrystallization, preparatorythin-layer chromatograph, preparatory high-pressure liquidchromatography, and others known in the art. A skilled person will alsorealize, that where appropriate, protecting groups for functional groupscan be used according to methods known in the art (see, e.g. [Ref 8] and[Ref 9])

Example 1 Synthesis of Exemplary Naphthalene-Based Photoacid Compounds

Described below is the synthesis of compound 1, as seen in FIG. 3.

Synthesis of Compound 3

To a 0.1 M solution of 3,4-dihydroxynaphthalene (2) in drydichloromethane (DCM) under argon is added at 0° C. 2.8 eq triethylamine(TEA) followed by chloroacetyl chloride (1.1 eq). The solution isallowed to warm to room temperature over one hour, then refluxed fourhours. Upon completion, the reaction is diluted with water, andextracted with DCM. The combined organics are washed with brine, dried,filtered and concentrated in-vacuo to afford the product (3).

A skilled person will realize that other chloroacyl chlorides can beselected to increase the ring size of the lactone thereby being able toproduce different values of n in the photoacid compounds of Formula (I).By way of example, 3-chloropropionyl chloride and 4-chlorobutyrylchloride can be used in place of chloroacetyl chloride to providephotoacid compounds of Formula (I) with values of n of 2 and 3,respectively.

A skilled person will also realize that the above reaction is notlimited to 3,4-dihydroxynaphthalene and that the above strategy can beapplied to other ortho dihydroxyaryl and heteroaryl molecules to providelight absorbing moieties with different functional groups on the lightabsorbing moiety.

A skilled person will also realize that hydroxyl groups can be placed onan arene or heteroarene using methods known to a skilled person (e.g.aromatic substitution reactions). By way of example, an aryl orheteroaryl ring can be subjected to nitration/reduction reactions toafford ortho diamino aryl or heteroaryl rings which can then besubjected to the Sandmeyer reaction (see, e.g. [Ref 10]) using water toconvert the amino groups into hydroxyl groups to afford ortho dihydroxyaryl and heteroaryl molecules.

Synthesis of Compound 4

Lactone 3 is dissolved in dry tetrahydrofuran (THF; 0.2 M) under argonand cooled to 0° C. Methylmagnesium bromide (MeMgBr; 2.2 eq, 3.0 M indiethyl ether) is added dropwise and the reaction is allowed to warm toroom temperature. After one hour, a solution of hydrocinnamoyl chloride(2.2 eq) in dichloromethane is added dropwise, and the mixture isstirred overnight. Upon completion, the reaction is quenched withsaturated aqueous sodium bicarbonate, and extracted withdichloromethane. The combined organics are dried over MgSO₄, filteredand concentrated in-vacuo. The crude is flashed on silica-gel elutingwith 10% ethyl acetate (EtOAc) in hexane to yield the product (4) as acrude oil.

A skilled person would recognize that additional Grignard reagents canbe chosen such that groups other than methyl can be substituted in thepositions corresponding to R¹ and R² in Formulas (I)-(II) describedherein. A skilled person would also recognize that a bis-Grignardreagent could be used to synthesize a compound in which R¹ and R² arethey are linked together to form a cyclic moiety. Such an exemplaryreaction is:

and an exemplary procedure would be as follows [Ref 11]: to a solutionof magnesium turnings (10 eq) in dry THF, 1,4-dibromobutane (2.2 eq, 0.2M) is added and the solution is gently heated until reaction isinitiated. After 1 hour, the solution is transferred via cannula into astirred solution of 25 (1.0 eq, 0.2 M) in dry THF under Ar at 0° C. Thereaction is allowed to warm to room temperature over 1 hour. To thesolution is then added the acid chloride (2.2 eq, 0.2 M) as a solutionin DCM. The mixture is stirred at room temperature overnight, thenquenched with water. The mixture is extracted with DCM, and the combinedorganics are dried with MgSO4, filtered and concentrated in-vacuo. Theresulting residue is taken up in 1:1 THF-MeOH, and cooled to 0° C.Aqueous LiOH (3 eq, 1 M) is added dropwise, and the reaction is warmedto room temperature. After stirring 1 hour, the reaction is quenchedwith aq. citric acid, extracted DCM, dried MgSO4, filtered, andconcentrated in-vacuo. The residue is purified by silica gelchromatography.

Additionally a skilled person would recognize that the acid chlorideused in the reaction can comprise the payload compound (R³) and thatpayload compounds other than the phenylethyl payload of compound 4a canbe incorporated by choice of the appropriate acid chloride. A skilledperson will also recognize that acid anhydrides, activated esters, andother activated carboxylic acid derivatives can be used instead of anacid chloride.

Synthesis of Photoacid Compound 1

Diester 4 (0.1 M) is dissolved in 1:1 THF-methanol (MeOH) and cooled to0° C. An aqueous solution of LiOH (3.0 eq, 1.0 M) is added dropwise andthe reaction is warmed to room temperature. After 2.5 hours, thereaction is quenched with aqueous citric acid, and extracted withdichloromethane. The combined organics are dried over MgSO₄, filteredand concentrated in-vacuo. The crude is flashed on silica-gel elutingwith 20% EtOAc in hexane to yield the product (1) as a clear oil.

Example 2 Possible Synthesis of Acene-Based Photoacid Compounds

A skilled person would recognize that the synthesis of thenaphthalene-based photoacid compound 1 in Example 1 can be modified tosynthesize acene-based photoacid compounds with more than two fused arylrings. For example, a skilled person could apply the methods of Lin etal. (“Iterative synthesis of acenes via homo-elongation” Chem. Commun.2009(7): 803-805) to perform the reaction:

to provide an acene of desired length analogous to compound 2 in Example1, which could then be carried through the synthetic steps of Example 1.A skilled person would also recognize that the aldehyde and/or nitrilegroups (R) in compound c can be converted to other functional groups(e.g. alcohols, esters, amines, and others identifiable to a skilledperson) for use in functionalizing the final photoacid compound productthough standard reaction conditions known to a skilled person (e.g.reduction with lithium aluminum hydride, diisobutyl aluminum hydride,and others identifiable to a skilled person).

A skilled person will also realize that the aldehyde groups (R) can befurther converted into amines (e.g., by reductive amination; see, e.g.,[Ref 12]). The amines can further be functionalized by standard peptidecoupling techniques (see e.g. [Ref 13]) with sulfonate peptides such as,for example:

to, for example, increase water solubility (see e.g., [Ref 14] and [Ref15]).

In in some embodiments, the substituent of compound 49 can be added to apendent functional group (e.g. an amine) on the light absorbing moiety(see Examples 1-4). In particular, such a substituent can provide, forexample, a compound according to Formula (XX):

wherein R is CH₂NH₂ or another moiety according such as 49, and n isbetween 0 and 5; or a compound according to Formula (XXI):

Example 3 Synthesis of Cyanine (Cy5)-Based Photoacid Compound 5

Described below is the synthesis of photoacid compound 5 as shown inFIG. 5. Synthesis of compound 7

3,4-dimethoxyaniline (6; 0.1 M) is dissolved in 1:1 HCl—H₂O and cooledto −10° C. under argon. A chilled aqueous solution of NaNO₂ (1.1 eq) isadded slowly via syringe, ensuring that the reaction maintains atemperature below 0° C. After stirring 30 minutes, a chilled solution of5 nCl₂ (3 eq, 2.0 M) in concentrated HCl followed by 3-methyl-2-butanone(3 eq) is added. The mixture is stirred 30 minutes, then quenched into avigorously stirred solution of aqueous sodium bicarbonate and EtOAc.After extraction with EtOAc, the combined organics are dried with MgSO₄,filtered, and concentrated in-vacuo. The residue is taken up in AcOH(0.1 M), and additional 3-methyl-2-butanone (3 eq) is added. Thereaction is stirred overnight at room temperature, then concentratedin-vacuo. The crude is flashed directly on silica-gel eluting with 75%EtOAc in hexane to obtain the product (7) as a brown oil.

Synthesis of Compound 8

Dimethoxyindolenine 7 (0.1 M) is dissolved in dry DCM under argon, andcooled to 0° C. BBr₃ (2.2 eq) is added dropwise, and the mixture isallowed to warm to r.t. After stirring 3 hours, the reaction is dilutedin water, and adjusted to pH 5 using solid sodium acetate. The mixtureis extracted with DCM, and the combined organics are dried over Na₂SO₄,filtered, and concentrated in-vacuo. The residue is flashed on 5% MeOHin DCM with 1% acetic acid to obtain the desired product (8) as a brownsolid.

Synthesis of Compound 9

To a solution of 8 in dry DCM (1 eq, 0.1 M) under argon is added at 0°C. triethylamine (2.2 eq) followed by chloroacetylchloride (1.1 eq). Thesolution is allowed to warm to room temperature over one hour, thenrefluxed for four hours. Upon completion, the reaction is diluted withwater, and extracted with DCM. The combined organics are washed withbrine, dried over Na₂SO₄, filtered and concentrated in-vacuo (See alsosynthesis of compound 3 in Example 1 and [Ref 16]).

Synthesis of Compound 10

Compound 9 is dissolved in dry THF (1 eq, 0.2 M) under argon and cooledto 0° C. MeMgBr (2.2 eq, 3.0 M in Et₂O) is added dropwise and thereaction is allowed to warm to room temperature. After one hour, asolution of hydrocinnamoyl chloride in DCM (2.2 eq, 0.2 M) is addeddropwise, and the mixture is stirred overnight. The reaction is thenquenched with saturated aqueous sodium bicarbonate, and extracted withDCM. The combined organics are dried over MgSO₄, filtered andconcentrated in-vacuo. The crude is flashed on silica gel eluting with10% EtOAc:Hexane to yield the product as a clear oil. See also synthesisof compound 4 in Example 1.

Synthesis of Compound 11

Compound 10 (1 eq, 0.1 M) and iodomethane (3 eq) are dissolved in dryDCM and stirred at reflux overnight. The mixture is then cooled to roomtemperature, concentrated in-vacuo, and used directly in the next step(see also [Ref 17]).

Synthesis of Compound 12

Compound 11 (1 eq, 0.2 M) and malondialdehyde bis(phenylimine).HCl (1.1eq) are dissolved in acetic anhydride and heated to 100° C. for 30minutes. The solution is cooled to room temperature, then a solution of23 (1 eq, 0.2 M) in pyridine is added. The reaction is stirredovernight, then concentrated in-vacuo. The residue is purified by silicagel chromatography (see also [Ref 18]).

Synthesis of Photoacid Compound 5

Compound 12 (1 eq, 0.1 M) is dissolved in 1:1 THF.MeOH. At 0° C., anaqueous solution of LiOH (3 eq, 1.0 M) is added dropwise and thereaction is warmed to room temperature. After 2.5 hours, the reaction isquenched with aqueous citric acid, and extracted with DCM. The combinedorganics are dried over MgSO₄, filtered and concentrated in-vacuo. Theproduct is purified by silica gel chromatography. See also synthesis ofcompound 1 in Example 1.

A skilled person will realize that additional functional groups can beplaced on the indole rings of the cyanine by choosing the appropriateaniline derivative similar to compound 6 above. Such differentfunctional groups can be selected, for example, to modulate thewavelength of light absorbed by the light absorbing molecule (see e.g.[Ref 1] and [Ref 19]), to attach groups for increasing water solubility(see e.g., Example 2), or to attach heavy atoms for increasing excitedstate lifetimes (see e.g., Example 4). A skilled person will alsorealize that different alkyl iodides can be selected as in the synthesisof compound 11 above to place different alkyl substituents on the indolenitrogens in the final cyanine, for example, to modulate the wavelengthof light absorbed by the light absorbing molecule (see e.g. [Ref 1] and[Ref 19]).

Example 4 Synthesis of Cyanine (Cy5)-Based Photoacids 13 and 14

Described below is the synthesis of photoacids 13 and 14 as shown inFIG. 5.

Synthesis of Compound 16

Compound 15 (1 eq, 1.0 M) is dissolved in 3:2 AcoH—H₂O and cooled to 0°C. Concentrated HNO₃ (1.1 eq) is added and the solution is heated to 65°C. for 10 minutes. After cooling to room temperature, the mixture isallowed to precipitate at 0° C. overnight. The crystalline product iscollected on a sintered glass funnel and washed with ice-cold water. Thesolid is then dissolved in an ice-cold solution of KOH (1.1 eq, 0.5 M in1:4 H₂O—MeOH) and allowed to warm to 50° C. for 15 minutes. Cooling to0° C. then affords a crystalline product that is filtered, washed withice water, and dried in-vacuo.

Synthesis of Compound 17

Compound 16 (1 eq) is dissolved in acetic acid (0.3 M) and added to asolution of NaNO₂ (1.1 eq, 2.0 M) in concentrated H₂SO₄, keeping thetemperature between 15-20° C. with an ice-bath. The resulting solutionis added over 5 minutes to a solution of CuBr (1.1 eq, 0.05 M in 1:1HBr—H₂O) heated at 80° C. After addition, the reaction mixture isallowed to cool to room temperature and extracted with DCM. The combinedorganics are dried over MgSO₄, filtered, and concentrated in-vacuo.

Synthesis of Compound 18

Compound 17 (1 eq, 0.1 M), iron powder (3 eq), and conc. HCl (5 eq) aredissolved in EtOH and heated to reflux. After stirring 5 hours, themixture is cooled to room temperature, made basic by addition of Na₂CO₃,and extracted with Et₂O. The combined organics are washed with water,dried over MgSO4, filtered, passed through a plug of silica gel, andconcentrated in-vacuo.

Synthesis of Compound 19

A suspension of 18 (1 eq, 0.2 M) in 1:1 conc. HCl—H₂O is cooled to −10°C. under Ar. A chilled solution of NaNO₂ (1.1 eq, 2.0 M) in H₂O isslowly added, keeping the temperature below 0° C. The solution isstirred at the temperature for 30 minutes, then a chilled solution of 5nCl₂ (3 eq, 2.0 M) in conc. HCl is added slowly. After addition, themixture is diluted in H₂O, and extracted Et₂O. The remaining organic ismade basic with NaOH, then extracted with Et2O. The combined organicsare dried over MgSO₄, filtered, and concentrated in-vacuo. The residueis taken up in AcOH, and 3-methyl-2-butanone (2.2 eq) is added. Themixture is refluxed overnight, then concentrated in-vacuo. The crude isflashed on silica gel eluting with 25% EtOAc, Hexane to obtain theproduct as a reddish oil.

Synthesis of Compound 20

Compound 19 (1 eq, 0.1 M) is dissolved in dry DCM under Ar and cooled to0° C. BBr₃ (1.1 eq) is added dropwise, and reaction stirred at thetemperature for 5 hours. The reaction is then diluted in H2O, extractedDCM, dried over MgSO4, and concentrated in-vacuo. The crude is flashedon 25% EtOAc:Hex to yield the product as a colorless oil.

Synthesis of Compound 21

Compound 20 is dissolved in iodomethane and refluxed overnight. Aftercooling to room temperature, the excess iodomethane is removed in-vacuo.The resulting residue is used without further purification.

Synthesis of Compounds 13 and 14

Compound 21 (1 eq, 0.2 M) and malondialdehyde bis(phenylimine.HCl (1.1eq) are dissolved in acetic anhydride and heated to 100° C. for 30minutes. The solution is cooled to room temperature, then a solution of23 (1 eq, 0.2 M) in pyridine is added. The reaction is stirredovernight, then concentrated in-vacuo. The residue is purified by silicagel chromatography to afford compound 14 with the phenoxy group as anacetate ester. The acetate ester of 14 (1 eq, 0.1 M) is dissolved in 1:1THF—MeOH. At 0° C., an aqueous solution of LiOH (3 eq, 1.0 M) is addeddropwise and the reaction is warmed to room temperature. After 2.5hours, the reaction is quenched with aqueous citric acid, and extractedwith DCM. The combined organics are dried over MgSO4, filtered andconcentrated in-vacuo. The product is purified by silica gelchromatography to afford compound 14. Compound 13 is made in the samemanner except using indolium 24 instead of 23.

Example 5 Decaging of Payload Compound

Compound 1a (see Example 1) was decaged using the following procedure.In a quartz cuvette, 1a (0.001 M) is dissolved in spectroscopic-gradeacetonitrile and irradiated at 300 nm using a 1-kW xenon arc lamp atroom temperature for 15 minutes. Aliquots are removed and analyzed byanalytical LC-MS utilizing a gradient elution of 10-100%acetonitrile-water over 10 minutes. The data shown represents t=0minutes in the lower LC-MS trace, t=15 minutes in the upper LC-MS trace.

Example 6 Synthesis of Photoacid Compound with X¹═C (Compound 31)

The linker with X¹ in Formulas (I) and (II) being C can be synthesizedaccording to the synthesis scheme of FIG. 7 (see, e.g., [Ref 20]). Askilled person will realize that the reactions below are not limited andcan be applied to molecules similar to compound 27.

Synthesis of Compound 28

3-hydroxy-2-naphthaldehyde (27; 1 eq, 0.1 M) is dissolved in dry DCMunder Ar and cooled to 0° C. A solution of AlCl₃ (1 eq, 1.0 M) in dryDCM is added, and the mixture is warmed to room temperature. Uponcompletion, the reaction is quenched with water, extracted with DCM,dried MgSO₄, filtered and concentrated.

A skilled person will realize that molecules similar to compound 27 canbe used. By way of example, in some molecules, the aldehyde may be aprecursor such as an alcohol or ester which may be oxidized or reduced,respectively, to afford an aldehyde.

Synthesis of Compound 29

The aldehyde (1 eq, 0.1 M) and (carbethoxymethylene)triphenylphosphorane(1.1 eq) are dissolved in dry xylene under Ar and refluxed 13 hours. Thesolution is diluted in water, and extracted EtOAc, dried MgSO₄, filteredand concentrated in-vacuo.

Synthesis of Compound 30

Compound 29 (1 eq, 0.1 M) and Raney Nickel (20%) are stirred in aqueousNaOH (1 M) at 90° C. for 1 hour. After cooling to r.t., the reaction isquenched with 1M HCl, and extracted with DCM. The combined organics aredried over MgSO₄, filtered and concentrated in-vacuo. The residue istaken up in dry benzene and refluxed with PTSA (1 eq) for 1 hour. Themixture is cooled, extracted with EtOAc, dried with MgSO₄, filtered andconcentrated in-vacuo.

Synthesis of Compound 31

Compound 30 (1 eq, 0.2 M) is dissolved in dry THF under Ar and cooled to0° C. A solution of MeMgBr (2.2 eq, 3.0 M in Et₂O) is added dropwise,and the reaction is allowed to warm to room temperature over 1 hour. Tothe solution is then added hydrocinnamoyl chloride (2.2 eq, 0.2 M) as asolution in DCM. The mixture is stirred at room temperature overnight,then quenched with water. The mixture is extracted with DCM, and thecombined organics are dried with MgSO4, filtered and concentratedin-vacuo. The resulting residue is taken up in 1:1 THF-MeOH, and cooledto 0° C. Aqueous LiOH (3 eq, 1 M) is added dropwise, and the reaction iswarmed to room temperature. After stirring 1 hour, the reaction isquenched with aq. citric acid, extracted DCM, dried MgSO₄, filtered, andconcentrated in-vacuo. The residue is purified by silica gelchromatography.

Example 7 General Synthesis of Cyanine-Based Photoacid Compounds

A skilled person will realize that cyanine-based [Ref 1, 19] photoacidcompounds in addition to those above can be synthesized using generalmethods. These general reaction methods are shown in FIG. 8A-F.

FIG. 8A shows a general synthetic strategy to synthesize photoacidcompounds of Formula (I) using a common precursor (ortho dihydroxyarene;32). In FIG. 8A, X′ and Y′ are linked together to form part of an areneor heteroarene. Compound 32 is then carried through the steps of Example1 and/or Example 3 to provide compound 34, shown in FIG. 8A with anoptional protecting group (PG; see [Ref 9] and [Ref 8]).

FIG. 8B shows a general synthetic scheme for the synthesis of closedchain cyanines with a variable-length polyene and variable heteroarylgroups. In FIG. 8B, commercially available precursors are converted tocompounds 36 and 35 (which can be converted into compound 36), andcompound 26 is converted into compound 37 (see, e.g. [Ref 21]). Incompounds 35, 36, and 37, X is nitrogen and Y is a heteroatom such as,for example, N, O, or S. Groups R^(a) and R^(b) in compounds 35, 36, and37 can be H, alkyl, or O-alkyl. In the alternative, R^(a) and R^(b) canbe linked together to form part of an arene or heteroarene. In somecases, when R^(a) and R^(b) are linked together to form part of an areneor heteroarene, the arene or heteroarene can be of the form of compound32 and can be carried through the steps of FIG. 8A. Similarly, whenR^(a) and R^(b) are O-alkyl, they may be subjected to Deprotectionconditions (see, e.g., synthesis of compound 8 in Example 3) to afford adihydroxylated arene or heteroarene can be of the form of compound 32.

FIG. 8C shows an exemplary application of the synthesis shown in FIG. 8Bto the general synthesis of photoacid compounds with cyanine lightabsorbing moieties. In FIG. 8C, compound 34 from FIG. 8A is carriedthrough the synthetic steps of FIG. 8B (with a deprotection step; see[Ref 9] and [Ref 8]) to afford a photoacidic compound (29) as hereindescribed with payload moiety R³.

FIG. 8D shows a photoactive molecule with a particular desiredabsorbance wavelength (compound 40) and an analogous photoactivecompound as herein described (compound 41) incorporating compound 40 asthe light absorbing moiety. Compound 40 can be synthesized using thequinolinium 44 (analogous to compound 36) using the methods of FIG. 8B.The synthesis of quinolinium 44 can be accomplished using the reactionsof FIG. 8E.

FIG. 8F shows the synthesis of photoacid compound 41 according to themethods of FIG. 8A, FIG. 8B, and FIG. 8E. Compound 45, which can besynthesized in one step from a commercially available compound, isconverted to dihydroxyquinoline 43 via the first reaction of FIG. 8E.Dihydroxyquinoline 43 can then be converted to compound 47 via thereactions of FIG. 8A. Compound 47 can then be converted to quinolinium48 via the second reaction of FIG. 8E. Quinolinium 48 can in turn beconverted to photoacid compound 41 via the last reaction of FIG. 8Bsimilar to what is done in FIG. 8C.

The examples set forth above are provided to give those of ordinaryskill in the art a complete disclosure and description of how to makeand use the embodiments photoacid compounds and related compositions,methods, and systems of the disclosure, and are not intended to limitthe scope of what the Applicants regard as their disclosure.Modifications of the above-described modes for carrying out thedisclosure can be used by persons of skill in the art, and are intendedto be within the scope of the following claims.

The entire disclosure of each document cited (including patents, patentapplications, journal articles including related supplemental and/orsupporting information sections, abstracts, laboratory manuals, books,or other disclosures) in the Background, Summary, Detailed Description,and Examples is hereby incorporated herein by reference. All referencescited in this disclosure are incorporated by reference to the sameextent as if each reference had been incorporated by reference in itsentirety individually. However, if any inconsistency arises between acited reference and the present disclosure, the present disclosure takesprecedence.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe disclosure claimed. Thus, it should be understood that although thedisclosure has been specifically disclosed by preferred embodiments,exemplary embodiments and optional features, modification and variationof the concepts herein disclosed can be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this disclosure as defined by the appended claims.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting. As used in this specification and the appended claims,the singular forms “a,” an and the include plural referents unless thecontent clearly dictates otherwise. The term “plurality” includes two ormore referents unless the content clearly dictates otherwise. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which the disclosure pertains.

The term “alkyl” as used herein refers to a linear, branched, or cyclicsaturated hydrocarbon group typically although not necessarilycontaining 1 to about 15 carbon atoms, or 1 to about 6 carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,octyl, decyl, and the like, as well as cycloalkyl groups such ascyclopentyl, cyclohexyl and the like. Generally, although again notnecessarily, alkyl groups herein contain 1 to about 15 carbon atoms. Theterm “cycloalkyl” intends a cyclic alkyl group, typically having 4 to 8,or 5 to 7, carbon atoms. The term “substituted alkyl” refers to alkylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in whichat least one carbon atom is replaced with a heteroatom. If not otherwiseindicated, the terms “alkyl” and “lower alkyl” include linear, branched,cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyland lower alkyl, respectively.

The term “hydrocarbyl” as used herein refers to any univalent radical,derived from a hydrocarbon, such as, for example, methyl or phenyl. Theterm “hydrocarbylene” refers to divalent groups formed by removing twohydrogen atoms from a hydrocarbon, the free valencies of which may ormay not be engaged in a double bond, typically but not necessarilycontaining 1 to 20 carbon atoms, in particular 1 to 12 carbon atoms andmore particularly 1 to 6 carbon atoms which includes but is not limitedto linear cyclic, branched, saturated and unsaturated species, such asalkylene, alkenylene alkynylene and divalent aryl groups, e.g.,1,3-phenylene, —CH₂CH₂CH₂-propane-1,3-diyl, —CH₂-methylene,—CH═CH—CH═CH—. The term “hydrocarbyl” as used herein refers to univalentgroups formed by removing a hydrogen atom from a hydrocarbon, typicallybut not necessarily containing 1 to 20 carbon atoms, in particular 1 to12 carbon atoms and more particularly 1 to 6 carbon atoms, including butnot limited to linear cyclic, branched, saturated and unsaturatedspecies, such as univalent alkyl, alkenyl, alkynyl and aryl groups e.g.ethyl and phenyl groups.

The term “heteroatom-containing” as in a “heteroatom-containing alkygroup” refers to a alkyl group in which one or more carbon atoms isreplaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur,phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly,the term “heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” and“heteroaromatic” respectively refer to “aryl” and “aromatic”substituents that are heteroatom-containing, and the like. It should benoted that a “heterocyclic” group or compound may or may not bearomatic, and further that “heterocycles” may be monocyclic, bicyclic,or polycyclic as described above with respect to the term “aryl.”Examples of heteroalkyl groups include alkoxyaryl,alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl,pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl,1,2,4-triazolyl, tetrazolyl, and others known to a skilled person, andexamples of heteroatom-containing alicyclic groups are pyrrolidino,morpholino, piperazino, piperidino, and other known to a skilled person.

The term “alkoxy” as used herein intends an alkyl group bound through asingle, terminal ether linkage; that is, an “alkoxy” group may berepresented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms.Analogously, “alkenyloxy” and “lower alkenyloxy” respectively refer toan alkenyl and lower alkenyl group bound through a single, terminalether linkage, and “alkynyloxy” and “lower alkynyloxy” respectivelyrefer to an alkynyl and lower alkynyl group bound through a single,terminal ether linkage.

The term “alkylamino” as used herein intends an alkyl group boundthrough a single terminal amine linkage; that is, an “alkylamino” may berepresented as —NH-alkyl where alkyl is as defined above. A “loweralkylamino” intends a alkylamino group containing 1 to 6 carbon atoms.The term “dialkylamino” as used herein intends two identical ordifferent bound through a common amine linkage; that is, a“dialkylamino” may be represented as —N(alkyl)₂ where alkyl is asdefined above. A “lower dialkylamino” intends a alkylamino wherein eachalkyl group contains 1 to 6 carbon atoms. Analogously, “alkenylamino”,“lower alkenylamino”, “alkynylamino”, and “lower alkynylamino”respectively refer to an alkenyl, lower alkenyl, alkynyl and loweralkynyl bound through a single terminal amine linkage; and“dialkenylamino”, “lower dialkenylamino”, “dialkynylamino”, “lowerdialkynylamino” respectively refer to two identical alkenyl, loweralkenyl, alkynyl and lower alkynyl bound through a common amine linkage.Similarly, “alkenylalkynylamino”, “alkenylalkylamino”, and“alkynylalkylamino” respectively refer to alkenyl and alkynyl, alkenyland alkyl, and alkynyl and alkyl groups bound through a common aminelinkage.

The term “aryl” as used herein, and unless otherwise specified, refersto an aromatic substituent containing a single aromatic ring or multiplearomatic rings that are fused together, directly linked, or indirectlylinked (such that the different aromatic rings are bound to a commongroup such as a methylene or ethylene moiety). Aryl groups can contain 5to 24 carbon atoms, or aryl groups contain 5 to 14 carbon atoms.Exemplary aryl groups contain one aromatic ring or two fused or linkedaromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether,diphenylamine, benzophenone, and the like. “Substituted aryl” refers toan aryl moiety substituted with one or more substituent groups, and theterms “heteroatom-containing aryl” and “heteroaryl” refer to arylsubstituents in which at least one carbon atom is replaced with aheteroatom, as will be described in further detail infra.

The term “arene”, as used herein, refers to an aromatic ring or multiplearomatic rings that are fused together. Exemplary arenes include, forexample, benzene, naphthalene, anthracene, and the like. The term“heteroarene”, as used herein, refers to an arene in which one or moreof the carbon atoms has been replaced by a heteroatom (e.g. O, N, or S).Exemplary heteroarenes include, for example, indole, benzimidazole,thiophene, benzthiazole, and the like. The terms “substituted arene” and“substituted heteroarene”, as used herein, refer to arene andheteroarene molecules in which one or more of the carbons and/orheteroatoms are substituted with substituent groups.

The terms “cyclic”, “cyclo-”, and “ring” refer to alicyclic or aromaticgroups that may or may not be substituted and/or heteroatom containing,and that may be monocyclic, bicyclic, or polycyclic. The term“alicyclic” is used in the conventional sense to refer to an aliphaticcyclic moiety, as opposed to an aromatic cyclic moiety, and may bemonocyclic, bicyclic or polycyclic.

The terms “halo”, “halogen”, and “halide” are used in the conventionalsense to refer to a chloro, bromo, fluoro or iodo substituent or ligand.

The term “substituted” as in “substituted alkyl,” “substituted aryl,”and the like, is meant that in the, alkyl, aryl, or other moiety, atleast one hydrogen atom bound to a carbon (or other) atom is replacedwith one or more non-hydrogen substituents.

Examples of such substituents include, without limitation: functionalgroups such as halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24alkenyloxy, C2-C24 alkynyloxy, C5-C24 aryloxy, C6-C24 aralkyloxy, C6-C24alkaryloxy, acyl (including C2-C24 alkylcarbonyl (—CO-alkyl) and C6-C24arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl, including C2-C24alkylcarbonyloxy (—O—CO-alkyl) and C6-C24 arylcarbonyloxy (—O—CO-aryl)),C2-C24 alkoxycarbonyl (—(CO)—O-alkyl), C6-C24 aryloxycarbonyl(—(CO)—O-aryl), halocarbonyl (—CO)—X where X is halo), C2-C24alkylcarbonato (—O—(CO)-β-alkyl), C6-C24 arylcarbonato (—O—(CO)—O-aryl),carboxy (—COOH), carboxylato (COO⁻), carbamoyl (—(CO)—NH2), mono-(C1-C24alkyl)-substituted carbamoyl (—(CO)—NH(C1-C24 alkyl)), di-(C1-C24alkyl)-substituted carbamoyl (—(CO)—N(C1-C24 alkyl)2), mono-(C5-C24aryl)-substituted carbamoyl (—(CO)—NH-aryl), di-(C5-C24aryl)-substituted carbamoyl (—(CO)—N(C5-C24 aryl)2), di-N—(C1-C24alkyl),N—(C5-C24 aryl)-substituted carbamoyl, thiocarbamoyl (—(C5-NH2),mono-(C1-C24 alkyl)-substituted thiocarbamoyl (—(CO)—NH(C1-C24 alkyl)),di-(C1-C24 alkyl)-substituted thiocarbamoyl (—(CO)—N(C1-C24 alkyl)2),mono-(C5-C24 aryl)-substituted thiocarbamoyl (—(CO)—NH-aryl), di-(C5-C24aryl)-substituted thiocarbamoyl (—(CO)—N(C₅-C₂₄ aryl)₂), di-N—(C₁-C₂₄alkyl),N—(C5-C24 aryl)-substituted thiocarbamoyl, carbamido(—NH—(CO)—NH₂), cyano(—C≡N), cyanato (—O—C≡H), thiocyanato (—S—C≡N),formyl (—(CO)—H), thioformyl ((CS)—H), amino (—NH2), mono-(C1-C24alkyl)-substituted amino, di-(C1-C24 alkyl)-substituted amino,mono-(C5-C24 aryl)-substituted amino, di-(C5-C24 aryl)-substitutedamino, C2-C24 alkylamido (—NH—(CO)-alkyl), C6-C24 arylamido(—NH—(CO)-aryl), imino (—CR═NH where R=hydrogen, C1-C24 alkyl, C5-C24aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to a skilledperson), C2-C20 alkylimino (CR═N(alkyl), where R=hydrogen, C1-C24 alkyl,C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to askilled person), arylimino (—CR═N(aryl), where R=hydrogen, C1-C20 alkyl,C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to askilled person), nitro (—NO2), nitroso (—NO), sulfo (—SO2-OH), sulfonato(—SO2-O⁻), C1-C24 alkylsulfanyl (—S-alkyl; also termed “alkylthio”),C5-C24 arylsulfanyl (—S-aryl; also termed “arylthio”), C1-C24alkylsulfinyl (—(SO)-alkyl), C5-C24 arylsulfinyl (—(SO)-aryl), C1-C24alkylsulfonyl (—SO2-alkyl), C5-C24 arylsulfonyl (—SO2-aryl), boryl(—BH2), borono (—B(OH)₂), boronato (—B(OR)₂ where R is alkyl or otherhydrocarbyl), phosphono (—P(O)(OH)2), phosphonato (—P(O)(O⁻)2),phosphinato (—P(O)(O⁻), phospho (—PO2), phosphino (—PH2), silyl (—SiR3wherein R is hydrogen or hydrocarbyl), and silyloxy (—O-silyl); and thehydrocarbyl moieties C1-C24 alkyl (e.g. C1-C12 alkyl and C1-C6 alkyl),C2-C24 alkenyl (e.g. C2-C12 alkenyl and C2-C6 alkenyl), C2-C24 alkynyl(e.g. C2-C12 alkynyl and C2-C6 alkynyl), C5-C24 aryl (e.g. C5-C14 aryl),C6-C24 alkaryl (e.g. C6-C16 alkaryl), and C6-C24 aralkyl (e.g. C6-C16aralkyl).

The term “acyl” refers to substituents having the formula —(CO)-alkyl,—(CO)-aryl, or —(CO)-aralkyl, and the term “acyloxy” refers tosubstituents having the formula —O(CO)-alkyl, —O(CO)-aryl, or—O(CO)-aralkyl, wherein “alkyl,” “aryl, and “aralkyl” are as definedabove.

The term “alkaryl” refers to an aryl group with an alkyl substituent,and the term “aralkyl” refers to an alkyl group with an arylsubstituent, wherein “aryl” and “alkyl” are as defined above. In someembodiments, alkaryl and aralkyl groups contain 6 to 24 carbon atoms,and particularly alkaryl and aralkyl groups contain 6 to 16 carbonatoms. Alkaryl groups include, for example, p-methylphenyl,2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl,7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.Examples of aralkyl groups include, without limitation, benzyl,2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl,4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl,4-benzylcyclohexylmethyl, and the like. The terms “alkaryloxy” and“aralkyloxy” refer to substituents of the formula —OR wherein R isalkaryl or aralkyl, respectively, as just defined.

When a Markush group or other grouping is used herein, all individualmembers of the group and all combinations and possible subcombinationsof the group are intended to be individually included in the disclosure.Every combination of components or materials described or exemplifiedherein can be used to practice the disclosure, unless otherwise stated.One of ordinary skill in the art will appreciate that methods, deviceelements, and materials other than those specifically exemplified can beemployed in the practice of the disclosure without resort to undueexperimentation. All art-known functional equivalents, of any suchmethods, device elements, and materials are intended to be included inthis disclosure.

Whenever a range is given in the specification, for example, atemperature range, a frequency range, a time range, or a compositionrange, all intermediate ranges and all subranges, as well as, allindividual values included in the ranges given are intended to beincluded in the disclosure. Any one or more individual members of arange or group disclosed herein can be excluded from a claim of thisdisclosure. The disclosure illustratively described herein suitably canbe practiced in the absence of any element or elements, limitation orlimitations, which is not specifically disclosed herein.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does notaccording to the guidance provided in the present disclosure. Forexample, the phrase “optionally substituted” means that a non-hydrogensubstituent may or may not be present on a given atom, and, thus, thedescription includes structures wherein a non-hydrogen substituent ispresent and structures wherein a non-hydrogen substituent is notpresent. It will be appreciated that the phrase “optionally substituted”is used interchangeably with the phrase “substituted or unsubstituted.”Unless otherwise indicated, an optionally substituted group may have asubstituent at each substitutable position of the group, and when morethan one position in any given structure may be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at every position. Combinations ofsubstituents envisioned can be identified in view of the desiredfeatures of the compound in view of the present disclosure, and in viewof the features that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

A number of embodiments of the disclosure have been described. Thespecific embodiments provided herein are examples of useful embodimentsof the disclosure and it will be apparent to one skilled in the art thatthe disclosure can be carried out using a large number of variations ofthe devices, device components, methods steps set forth in the presentdescription. As will be obvious to one of skill in the art, methods anddevices useful for the present methods can include a large number ofoptional composition and processing elements and steps.

In particular, it will be understood that various modifications may bemade without departing from the spirit and scope of the presentdisclosure. Accordingly, other embodiments are within the scope of thefollowing claims.

REFERENCES

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1. A photoacid compound comprising a light absorbing moiety attaching anpayload moiety through a linker moiety wherein the linker moiety is anorganic moiety comprising a geminal dialkyl moiety linked to an estergroup having a carbonyl oxygen, the carbonyl group of the esterattaching the payload moiety; the light absorbing moiety is an organicmoiety attaching the linker moiety in ortho position to a hydroxylgroup; and the linker is configured to present the carbonyl oxygen forreaction with the hydroxyl group.
 2. The photoacid compound of claim 1wherein the light-absorbing moiety is a substituted or unsubstitutedpolycyclic aromatic hydrocarbon, a substituted or unsubstituted closedchain cyanine, or a substituted or unsubstituted hemicyanine.
 3. Thephotoacid compound of claim 1, wherein the light absorbing moiety isable to absorb light at a wavelength of from about 900 nm to about 1100nm.
 4. The photoacid compound of claim 1, wherein the geminal dialkylmoiety can be joined together to form a cyclic moiety.
 5. The photoacidcompound of claim 1, wherein the linker moiety is a monoalkoxy or adialkoxy moiety in which an oxy group forms part of the ester grouphaving the carbonyl oxygen.
 6. The photoacid compound of claim 1,wherein the payload moiety is a substituted or unsubstituted alkyl,aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety.
 7. Aphotoacid compound according to formula (I):

wherein: R⁴ is a light-absorbing moiety presenting a hydroxyl group forinteraction with the carbonyl oxygen of the R³(CO)O group, wherein thelight-absorbing moiety is a substituted or unsubstituted polycyclicaromatic hydrocarbon, a substituted or unsubstituted closed chaincyanine, or a substituted or unsubstituted hemicyanine, and wherein thehydroxyl group is covalently bonded to the polycyclic aromatichydrocarbon, the closed chain cyanine, or the hemicyanine, and thehydroxyl group is in a position ortho to X¹; R³ is a payload moiety,wherein the payload moiety is a substituted or unsubstituted alkyl,aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety; X¹ isindependently selected from the group consisting of C and O; m isbetween 0 and 3; and R¹ and R² are independently C₁-C₆ alkyl groups,cycloalkyl, or substituted or unsubstituted hydrocarbylene groupswherein when R¹ and R² are substituted or unsubstituted hydrocarbylenegroups, R¹ and R² are linked together to form a cyclic moiety.
 8. Thephotoacidic compound according to claim 7, wherein X¹ is O and R¹ and R²are methyl, ethyl, or are linked together to form a cyclopentyl orcyclohexyl moiety.
 9. The photoacidic compound according to claim 7,wherein X¹ is C and R¹ and R² are methyl, ethyl, or are linked togetherto form a cyclopentyl or cyclohexyl moiety.
 10. The photoacid compoundof claim 7, wherein R⁴ has formula (II):

wherein n is between 0 and
 5. 11. The photoacidic compound according toclaim 10, wherein n is O.
 12. The photoacid compound of claim 7, whereinR⁴ has formula (III):

where n is between 0 and 5, and m is between 1 and
 3. 13. The photoacidof claim 12, wherein m is 2 and n is
 0. 14. The photoacid compound ofclaim 7, wherein R⁴ has formula (IV):

wherein R^(a) and R^(b) are independently H, alkyl, or O-alkyl; Y is N,O, or S; and p is between 1 and
 4. 15. The photoacid compound of claim14, wherein p is
 2. 16. The photoacid compound of claim 7, wherein R⁴has formula (V):

wherein R^(c) and R^(d) are alkyl substituents and q is between 1 and 4.17. The photoacid compound of claim 16, wherein q is
 2. 18. Thephotoacid compound of claim 7, wherein R⁴ has formula (VI):

wherein r is between 1 and
 4. 19. The photoacid compound of claim 18,wherein r is
 2. 20. The photoacid of claim 7, wherein R³ has thestructure of formula (VII):

wherein q is between 0 and 5; R^(α) is H, or substituted orunsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy,heteroaryl, hetroarylamino, and heteroaryloxy group; X is C or N; andwherein when q is greater than 1, each R^(α) is independent of the otherR^(α) substituents.
 21. The photoacid of claim 7, wherein R³ has thestructure of formula (VIII):

wherein: n is between 1 and 5; R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; andwherein when n is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.
 22. The photoacid of claim 7, wherein R³ has the structure offormula (IX):

wherein: p is between 1 and 5; R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy,wherein R^(δ) is H, substituted or unsubstituted alkyl, acyl, aryl; andwherein when p is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.
 23. The photoacid of claim 7, wherein R³ has the structure offormula (X):

wherein m is between 1 and 5; R^(α), R^(β), and R^(γ) are independentlyH, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl,arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; andwherein when m is greater than 1, the R^(α) and R^(β) of eachC(R^(α))(R^(β)) unit are independent of the R^(α) and R^(β) of the otherunits.
 24. The photoacid of claim 7, wherein R³ has the structure offormula (XI):

wherein q is between 0 and 4; R^(α) is H, or substituted orunsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy,heteroaryl, hetroarylamino, and heteroaryloxy; ε is a substituted orunsubstituted hydrocarbylene, X is C or N; and wherein when q is greaterthan 1, each R^(α) is independent of the other R^(α) substituents. 25.The photoacid compound of claim 7, wherein R³ has a structure selectedfrom the group consisting of formulas (XII)-(XVII):


26. A method to deliver a compound, comprising providing a cagedcompound, the caged compound being caged as a payload moiety within thephotoacid compound of claim 1, the photoacid compound being in a groundstate in which the hydrogen substituted heteroatom presented on thelight absorbing moiety of the photoacid compound has a ground statepK_(a); and uncaging the caged compound by irradiating the photoacidcompound with light at a wavelength suitable to promote the photoacidcompound to an excited state wherein the hydrogen substituted heteroatompresented on the light absorbing moiety of the photoacid compound has anexcited state pK_(a) lower than the ground state pK_(a).
 27. The methodaccording to claim 26, wherein the wavelength of the light is greaterthan 750 nm.
 28. The method according to claim 26, wherein irradiatingthe photoacid compound is performed with light at a wavelength betweenabout 750 and about 1400 nm.
 29. The method according to claim 26,wherein irradiating the photoacid compound is performed with light at awavelength between about between about 900 and about 1100 nm.
 30. Themethod according to claim 26, wherein irradiating the photoacid compoundis performed with light at a wavelength less than about 750 nm.
 31. Asystem to deliver a compound, the system comprising at least two of: onephotoacid compound of claim 1; and a light source suitable to irradiatelight at a suitable wavelength, for simultaneous, combined or sequentialuse in a method to deliver a compound, comprising providing a cagedcompound, the caged compound being caged as a payload moiety within aphotoacid compound of claim 1, the photoacid compound being in a groundstate in which the hydrogen substituted heteroatom presented on thelight absorbing moiety of the photoacid compound has a ground statepK_(a); and uncaging the caged compound by irradiating the photoacidcompound with light at a wavelength suitable to promote the photoacidcompound to an excited state wherein the hydrogen substituted heteroatompresented on the light absorbing moiety of the photoacid compound has anexcited state pK_(a) lower than the ground state pK_(a).